The replacement of hydroxyl groups by fluorine atoms on hexopyranose scaffolds may allow access to the discovery of new chemical entities possessing unique physical, chemical and ultimately even biological properties. The prospect of significant effects generated by such multiple and controlled substitutions encouraged us to develop diverse synthetic routes towards the stereoselective synthesis of polyfluorinated hexopyranoses, six of which are unprecedented. Hence, we report the synthesis of heavily fluorinated galactose, glucose, mannose, talose, allose, fucose, and galacturonic acid methyl ester using a Chiron approach from inexpensive levoglucosan. Structural analysis of single-crystal X-ray diffractions and NMR studies confirm the conservation of favored 4C1 conformation for fluorinated carbohydrate analogs, while a slightly distorted conformation due to repulsive 1,3-diaxial F···F interaction is observed for the trifluorinated talose derivative. Finally, the relative stereochemistry of multi-vicinal fluorine atoms has a strong effect on the lipophilicities (logP).

In this work,w es ynthesized all mono-, di-, and trifluorinated glucopyranose analogues at positions C-2, C-3, C-4, and C-6. This systematic investigation allowed us to perform direct comparison of 19 Fr esonances of fluorinated glucose analoguesa nd also to determine their lipophilicities. Compounds with af luorine atom at C-6 are usually the most hydrophilic, whereas those with vicinal polyfluorinated motifs are the most lipophilic. Finally, the solvation energies of fluorinated glucosea naloguesw ere assessed for the first time by using density functional theory.T hism ethoda llowedt he log P prediction of fluoroglucose analogues, whichw as comparable to the Clog P valueso btained from various web-basedp rograms.

The replacement of hydroxyl groups by fluorine atoms on hexopyranoside scaffolds may allow access to invaluable tools for studying various biochemical processes. As part of ongoing activities toward the preparation of fluorinated carbohydrates, a systematic investigation involving the synthesis and biological evaluation of a series of mono‐ and polyfluorinated galactopyranosides is described. Various monofluorogalactopyranosides, a trifluorinated, and a tetrafluorinated galactopyranoside have been prepared using a Chiron approach. Given the scarcity of these compounds in the literature, in addition to their synthesis, their biological profiles were evaluated. Firstly, the fluorinated compounds were investigated as antiproliferative agents using normal human and mouse cells in comparison with cancerous cells. Most of the fluorinated compounds showed no antiproliferative activity. Secondly, these carbohydrate probes were used as potential inhibitors of galactophilic lectins. The first transverse relaxation‐optimized spectroscopy (TROSY) NMR experiments were performed on these interactions, examining chemical shift perturbations of the backbone resonances of LecA, a virulence factor from Pseudomonas aeruginosa. Moreover, taking advantage of the fluorine atom, the 19F NMR resonances of the monofluorogalactopyranosides were directly monitored in the presence and absence of LecA to assess ligand binding. Lastly, these results were corroborated with the binding potencies of the monofluorinated galactopyranoside derivatives by isothermal titration calorimetry experiments. Analogues with fluorine atoms at C‐3 and C‐4 showed weaker affinities with LecA as compared to those with the fluorine atom at C‐2 or C‐6. This research has focused on the chemical synthesis of “drug‐like” low‐molecular‐weight inhibitors that circumvent drawbacks typically associated with natural oligosaccharides.

In this work, we have developed a simple synthetic approach using Et3N·3HF as an alternative to the DAST reagent. We controlled the stereochemistry of the nucleophilic fluorination at C4 of 1,6-anhydro-2,3-dideoxy-2,3-difluoro-4-O-triflate-β-ᴅ-talopyranose using Et3N·3HF or in situ generated Et3N·1HF. The influence of the fluorine atom at C2 on reactivity at C4 could contribute to a new fluorine effect in nucleophilic substitution. Finally, with the continuous objective of synthesizing novel multi-vicinal fluorosugars, we prepared one difluorinated and one trifluorinated alditol analogue.

Fluorinated carbohydrates are invaluable tools to study various biochemical processes. Herein, we describe a new strategy to access orthogonally protected 3-deoxy-3-fluorogalactopyranose and acetylated 4-deoxy-4-fluorogalactopyranose. Starting from inexpensive levoglucosan, most reactions were performed on a gram scale and allowed excellent regio- and stereocontrol with a minimal use of protection/deprotection cycles. Hence, we developed practical alternatives to the decade-long reported method to access both 3-deoxy-3-fluoro- and 4-deoxy-4-fluorogalactopyranose.